PROJECT 3 DESCRIPTION: The generation of an effective AIDS vaccine is complicated by our limited knowledge of the correlates of immune protection during HIV and SIV infection. Here we propose to study the cellular immune responses generated by different immunization strategies that include MVA- and Adenovirus/MVA-based HIV and SIV vaccines, and to compare them with those generated during natural HIV and experimental SIV infection. An improved understanding of the determinants and generation of protective cellular immune responses against a model virus infection have emerged from studies of LCMV infection in mice. These studies elucidated the crucial distinction between central memory T cells (Tcm) and effector memory T cells (Tem), and described the predominant role of Tcm cells in protecting from re-challenge. Using these insights, in combination with emerging insights into functional defects of memory T cells following HIV infection, we seek to determine if responses elicited by vaccination result in a better ability to develop and maintain functional, durable Tcm-mediated responses to HlV and SlV antigens. The phenotypes and functions of the HIV-specific Tem and Tcm cell populations induced by different vaccination regimens will be defined, and compared to the memory T cell responses that arise following HIV and SIV infections as well as those that will be observed after SIV-challenge of previously vaccinated macaques. In this way, we will explore potential mechanisms by which vaccine-induced HIV- and SIV-specific memory T cell responses may be more effective in controlling virus replication than those following infection, and less likely to precipitate immunopathologic consequences. In all, these studies are aimed at defining markers that will predict vaccine effectiveness in inducing host responses that can contain virus replication, prolong disease-free survival, and decrease secondary transmission. Definition of the characteristics of such effective immune responses will ideally advance our understanding of the correlates of protection to be pursued in future efforts of AIDS vaccine development.